Abstract Hypertension, which affects about 30% of adults, has a worldwide prevalence estimated at 1 billion individuals and contributes to approximately 7.1 million deaths per year (1). Morbidity and mortality in hypertension are strongly associated with target organ dysfunction and failure. The genetic bases for hypertension have been difficult to decipher; multiple genes are likely to influence elevation in blood pressure and vulnerability to develop hypertension, but only about 5% of the genetic factors that are believed to influence blood pressure have been identified (2). The kidney is central in the regulation of blood pressure (3). G protein-coupled receptors (GPCR) expressed in the kidney regulate the tubular reabsorption of vital molecules from the filtrate, especially sodium, to maintain a normal blood pressure. GPR37L1, an orphan receptor, which is closely related to GPR37 (4), and is expressed predominantly in brain but also found in heart and stomach, and to a lesser extent in the kidney (4-6). Our preliminary data show for the first time that GPR37L1 mRNA and protein are expressed in mouse renal proximal tubule but not in collecting duct cells and localized specifically at the brush border membrane. Prosaposin (PSAP) and prosaptide, a 14 amino acid synthetic peptide derived from PSAP, (7) were recently been identified as ligand for the receptor. Our in vivo live imaging of human renal proximal tubule cells expressing GPR37L1 tagged with GFP corroborated this finding. In addition, mice chronically fed with a high salt diet have increased renal expression of PSAP. In human renal proximal tubule cells, over expression of GPR37L1 increased intracellular sodium accumulation that was blunted by NHE3 inhibition. Conversely, silencing of GPR37L1 decreased intracellular sodium accumulation. Overexpression of GPR37L1 in human renal proximal tubule cells increased sodium/hydrogen exchanger type 3 (NHE3) and aquaporin 1 (AQP1) expression, as well as phosphorylation of ERK1/2, AKT and STAT1, while GPR37L1 silencing in these cells decreased NHE3 and AQP1 expression, indicating that GPR37L1 increases sodium transport at the proximal tubule luminal membrane, via NHE3, and facilitates water reabsorption via AQP1. Moreover, renal specific silencing of GPR37L1 in vivo in mice decreased blood pressure, and decreased renal NHE3 and AQP1 expression, indicating that renal GPR37L1 and PSAP system regulate blood pressure. These data suggest that that GPR37L1 and PSAP play an important role in sodium and water balance and blood pressure regulation by modulating the expression of NHE3 and AQP1 via ERK1/2, AKT and /or STAT1 signal transduction pathways. In this proposal, we will test the overall novel hypothesis that renal GPR37L1 is a positive regulator of the expression and function of both NHE3 and AQP1.